P 132 - SIRT3 protects against palmitate-induced neuronal lipotoxicity

Abstract

The mitochondrial NAD+-dependent deacetylase Sirtuin3 orchestrates adaptive responses to metabolic stresses and exerts antioxidative capacities. As a result, SIRT3 knockout mice exhibit mitochondrial dysfunction and are prone to neurodegeneration. High levels of circulating free fatty acids are associated with mitochondrial dysfunction, oxidative stress and insulin resistance (IR), features of metabolic and neurodegenerative diseases. We show that neurons treated with the saturated fatty acid palmitic acid exhibit reduced SIRT3 expression, increased protein acetylation and mitochondrial dysfunction. We hypothesized that SIRT3 protects neurons from lipid-induced mitochondrial dysfunction and IR as observed in metabolic disorders. Thus, we overexpressed SIRT3 in mouse neurons (SIRT3OE) and analyzed its function on neuronal metabolism under basal and lipotoxic conditions. Strikingly, SIRT3OE in neurons caused IR, mitochondrial dysfunction and ER stress, compared to control. Yet in palmitate-induced lipotoxic conditions, SIRTOE rescued palmitate-induced IR as well as palmitate-induced ER stress and mitochondrial dysfunction. In summary, in an unstressed state, elevated SIRT3 levels in neurons cause IR and cell stress, while protecting against palmitate-induced cell stress and improving insulin sensitivity, pointing to a crucial role for the precise regulation of SIRT3 in the brain.